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Impact of LDL-cholesterol Lowering on Platelet Activation

Sponsor
Columbia University (Other)
Overall Status
Terminated
CT.gov ID
NCT03331666
Collaborator
Amgen (Industry)
4
Enrollment
1
Location
2
Arms
14.6
Actual Duration (Months)
0.3
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary goal is to assess the impact of Evolocumab therapy on platelet function of familial hypercholesterolemia (FH) patients in a randomized, double blind study. Evolocumab is a humanized monoclonal antibody that targets circulating PCSK9, increases hepatic LDL receptor, decreases plasma LDL cholesterol and reduces risk of cardiovascular events. Evolocumab (brand name Rapatha) has been approved by FDA along with diet and maximally tolerated statin therapy in adults with FH or atherosclerotic heart or blood vessel problems, who need additional lowering of LDL cholesterol.

The secondary goal is to determine if platelet activation or the response to Evolocumab therapy is modified by rs3184504 polymorphism. The investigators believe that these investigations will complement ongoing studies to demonstrate that Evolocumab reduces athero-thrombotic risk and aid the decision-making as to whether Evolocumab can reduce the atherothrombotic risk in acute coronary syndrome (ACS) patients.

Condition or Disease Intervention/Treatment Phase
Phase 4

Detailed Description

Hyperlipidemia as exemplified by familial hypercholesterolemia is associated with increased platelet activation and an underlying pro-coagulant state. Hyperlipidemia primes platelets and increases platelet activation in response to various agonists. Plasma cholesterol levels appear to have a critical role in modulating platelet activity as hypercholesterolemia increases platelet activation more potently than hypertriglyceridemia. Increased platelet reactivity may contribute to the increased risk of atherothrombosis associated with hypercholesterolemia. Plasma levels of platelet activation markers such as thrombin-antithrombin complex (TAT), soluble P-selectin (sP-selectin), soluble CD40L (sCD40L) or P-selectin exposure at surface of platelets are increased in hypercholesterolemic patients. Increased levels of the platelet activation markers are associated with increased platelet membrane cholesterol content in hypercholesterolemia.Statins may show antithrombotic properties.

Study Design

Study Type:
Interventional
Actual Enrollment :
4 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Prevention
Official Title:
Impact of LDL-cholesterol Lowering on Platelet Activation
Actual Study Start Date :
Nov 16, 2018
Actual Primary Completion Date :
Feb 4, 2020
Actual Study Completion Date :
Feb 4, 2020

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Evolocumab

Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 14 until Day 196.

Drug: Evolocumab
140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia
Other Names:
  • REPATHA

    		•
    Placebo Comparator: Placebo

    Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 28 until Day 196.

    Drug: Evolocumab
    140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia
    Other Names:
  • REPATHA

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (P2Y12 Reaction Units (PRU)) [Day 7, Day 14, Day 21, Day 28, Day 84]

      ADP- or arachidonic acid-stimulated platelet aggregation as assessed by the commercially-available VerifyNow P2Y12 (VerifyNow PRUTest) will be performed. Unit: PRU

    2. Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (Aspirin Reaction Unit (ARU)) [Day 7, Day 14, Day 21, Day 28, Day 84]

      ADP- or arachidonic acid-stimulated platelet aggregation as assessed by the commercially-available VerifyNow Aspirin assay (Accriva Diagnostics) will be performed. Unit: Aspirin Reaction Unit (ARU)

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Subjects who have a clinical diagnosis of familial hypercholesterolemia (FH)

    • Subjects who are referred to Dr. Ginsberg's Lipid Practice for treatment with PCSK9 inhibitor

    • Subjects with LDL cholesterol levels >100 mg/dl on baseline treatment with statins and/or ezetimibe

    Exclusion Criteria:
    • Children under 18 years of age

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Columbia University Medical Center New York New York United States 10032

    Sponsors and Collaborators

    • Columbia University
    • Amgen

    Investigators

    • Study Director: Henry Ginsberg, MD, Columbia University
    • Principal Investigator: Nan Wang, PhD, Columbia University

    Study Documents (Full-Text)

    More Information

    Publications

    Responsible Party:
    Nan Wang, Associate Professor of Medical Sciences (in Medicine) at the Columbia University Medical Center, Columbia University
    ClinicalTrials.gov Identifier:
    NCT03331666
    Other Study ID Numbers:
    • AAAR1041
    First Posted:
    Nov 6, 2017
    Last Update Posted:
    Apr 1, 2021
    Last Verified:
    Mar 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    No
    Keywords provided by Nan Wang, Associate Professor of Medical Sciences (in Medicine) at the Columbia University Medical Center, Columbia University
    Hyperlipidemia, Hypercholesterolemia, atherothrombosis
    Additional relevant MeSH terms:
    Hyperlipoproteinemia Type II
    Hypercholesterolemia
    Evolocumab

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Evolocumab Placebo
    Arm/Group Description Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 14 until Day 196. Evolocumab: 140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 28 until Day 196. Evolocumab: 140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia
    Period Title: Overall Study
    STARTED 2 2
    COMPLETED 0 0
    NOT COMPLETED 2 2

    Baseline Characteristics

    Arm/Group Title Evolocumab Placebo Total
    Arm/Group Description Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 14 until Day 196. Evolocumab: 140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 28 until Day 196. Evolocumab: 140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia Total of all reporting groups
    Overall Participants 2 2 4
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    1
    50%
    0
    0%
    1
    25%
    >=65 years
    1
    50%
    2
    100%
    3
    75%
    Sex: Female, Male (Count of Participants)
    Female
    1
    50%
    1
    50%
    2
    50%
    Male
    1
    50%
    1
    50%
    2
    50%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    2
    100%
    0
    0%
    2
    50%
    Not Hispanic or Latino
    0
    0%
    2
    100%
    2
    50%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    2
    100%
    2
    100%
    4
    100%

    Outcome Measures

    1. Primary Outcome
    Title Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (P2Y12 Reaction Units (PRU))
    Description ADP- or arachidonic acid-stimulated platelet aggregation as assessed by the commercially-available VerifyNow P2Y12 (VerifyNow PRUTest) will be performed. Unit: PRU
    Time Frame Day 7, Day 14, Day 21, Day 28, Day 84

    Outcome Measure Data

    Analysis Population Description
    Adult male and female subjects who have a clinical diagnosis of familial hypercholesterolemia and referred for treatment with PCSK9 inhibitor, with LDL cholesterol levels ≥70 mg/dl on baseline treatment with statins and/or ezetimibe or intolerant to statin and/or ezetimibe. Of the four participants reported in this study, one participant per arm had ADP assessed by PRU Test (evolocumab and placebo arms) and one participant per arm had ADP assessed by Aspirin assay (evolocumab and placebo arms).
    Arm/Group Title Evolocumab Placebo
    Arm/Group Description Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 14 until Day 196. Evolocumab: 140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 28 until Day 196. Evolocumab: 140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia
    Measure Participants 1 1
    P2Y12 Test, Day 7
    266
    216
    P2Y12 Test, Day 14
    268
    226
    P2Y12 test, Day 21
    268
    233
    P2Y12 Test, Day 28
    276
    225
    P2Y12 Test, Day 84
    256
    267
    2. Primary Outcome
    Title Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (Aspirin Reaction Unit (ARU))
    Description ADP- or arachidonic acid-stimulated platelet aggregation as assessed by the commercially-available VerifyNow Aspirin assay (Accriva Diagnostics) will be performed. Unit: Aspirin Reaction Unit (ARU)
    Time Frame Day 7, Day 14, Day 21, Day 28, Day 84

    Outcome Measure Data

    Analysis Population Description
    Adult male and female subjects who have a clinical diagnosis of familial hypercholesterolemia and referred for treatment with PCSK9 inhibitor, with LDL cholesterol levels ≥70 mg/dl on baseline treatment with statins and/or ezetimibe or intolerant to statin and/or ezetimibe. Of the four participants reported in this study, one participant per arm had ADP assessed by PRU Test (evolocumab and placebo arms) and one participant per arm had ADP assessed by Aspirin assay (evolocumab and placebo arms).
    Arm/Group Title Evolocumab Placebo
    Arm/Group Description Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 14 until Day 196. Evolocumab: 140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 28 until Day 196. Evolocumab: 140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia
    Measure Participants 1 1
    Aspirin Test, Day 7
    521
    432
    Aspirin Test Day 14
    608
    401
    Aspirin Test, Day 21
    533
    490
    Aspirin Test, Day 28
    530
    512
    Aspirin Test, Day 84
    406
    386

    Adverse Events

    Time Frame 4 months
    Adverse Event Reporting Description
    Arm/Group Title Evolocumab Placebo
    Arm/Group Description Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 14 until Day 196. Evolocumab: 140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 28 until Day 196. Evolocumab: 140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia
    All Cause Mortality
    Evolocumab Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/2 (0%) 0/2 (0%)
    Serious Adverse Events
    Evolocumab Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/2 (0%) 0/2 (0%)
    Other (Not Including Serious) Adverse Events
    Evolocumab Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/2 (0%) 0/2 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dr. Nan Wang
    Organization Columbia University Irving Medical Center
    Phone 212-342-1761
    Email nw30@cumc.columbia.edu
    Responsible Party:
    Nan Wang, Associate Professor of Medical Sciences (in Medicine) at the Columbia University Medical Center, Columbia University
    ClinicalTrials.gov Identifier:
    NCT03331666
    Other Study ID Numbers:
    • AAAR1041
    First Posted:
    Nov 6, 2017
    Last Update Posted:
    Apr 1, 2021
    Last Verified:
    Mar 1, 2021